5.1　CEL-HYB Allele Discovery

CEL encodes carboxyl ester lipase（OMIM#114840），a digestive enzyme synthesized and secreted in abundance by the pancreatic acinar cells（Holmes and Cox 2011）.The CEL gene is highly polymorphic by virtue of a 33-bp variable number tandem repeat（VNTR）in its eleventh and last exon；the repeat number varies from 9 to 23 in the normal population，the most common allele containing 16 repeats（Lindquist et al.2002）.Single nucleotide deletions occurring within this VNTR region have been reported to cause autosomal dominant maturity-onset diabetes of the young（MODY）（Raeder et al.2006）.(https://www.daowen.com)

MODY is characterized by endocrine and exocrine dysfunctions of the pancreas.Therefore，Fjeld and colleagues analysed CEL as a candidate gene for chronic pancreatitis（Fjeld et al.2015）.They found that a hybrid allele（CELHYB），involving the CEL gene and its tandemly linked pseudogene CELP，was significantly overrepresented in chronic pancreatitis cases as compared with controls，firstly in a discovery cohort of patients with familial chronic pancreatitis and then in three replication cohorts of patients with ICP.This hybrid allele resulted from non-allelic homologous recombination（NAHR）occurring between CEL intron 10 and CELP intron 10'.The consequent replacement of the eleventh and last exon of CEL by CELP exon 11'was predicted to yield a premature stop codon within the third“pseudo”33-bp VNTR（Fig.6.la）.The truncated CPA1 enzyme is more stable than its wild-type counterpart and induced autophagy in cellular models（Fjeld et al.2015）.Autophagy is a homeostatic process or regulated destructive mechanism of the cell that disassembles unnecessary or dysfunctional components（Klionsky 2008）.It is widely implicated in many pathophysiological processes such as cancer，metabolic and neurodegenerative disorders，and cardiovascular and pulmonary diseases（Choi et al.2013）.Findings from experimental models and genetically altered mice demonstrated that this principal cellular degradative pathway was also impaired in pancreatitis（Gukovskaya and Gukovsky 2012）.